Claire Redfield in the video games is in a never-ending search for her brother Chris. When the main plot of the film was planned, the original purpose of the trip to Alaska would be the reunion of Claire with her brother. The Chris Redfield subplot was scrapped and the voyage to Alaska was rescheduled as a simple quest for a safe haven.

Raccoon City is clearly Detroit, Michigan from the graphic about 6-7 minutes into the film. The Detroit river and Belle Isle are clearly discernible, as is the half moon shaped industrial park to the North (towards the left in the film).

The original script included some flashback sequences depicting the trial in the International Court of Geneva. The Umbrella executives were convicted for the genocide but the hearing came to an abrupt end when an army of undead barged into the courtroom.

The nightmares of Alice indicate that she has a mild psychic connection to her clones, since some of their memories are transferred into her subconscious. This element becomes important for the sequels.

There was much speculation that the well-known character from the video games, Leon Kennedy, would make a cameo and his role would expand in the upcoming fourth film. For a long time it was rumored that the known actor Jensen Ackles would be cast as Leon Kennedy, but this never happened.

The possibility of a third film in the franchise was first discussed when Resident Evil: Apocalypse (2004) opened at number 1 on the US box office, earning more than $23 million in its opening weekend.

The trademark double spiral-shaped injections (representing D.N.A.) now have two liquids instead of one. The one spiral contains the blue liquid (the T-virus) and the other one contains the green liquid (the antidote). The mixture is supposedly capable of bestowing the regenerative features of the T-virus but without succumbing to the atrocious side effects - mutation into an undead.

One of the few additions in the latest drafts of the script is the initial attack of the desert gang. Originally Alice would discover an abandoned TV station. She would watch old footage on the screens depicting the destruction of the world due to the global infection. Her narration would unfold at that point. When the script was rewritten this scene was dropped and it was substituted with the assault scene. The only remaining hint is the fact that Alice meets the deranged family in a decrepit TV station. Her narration was also rescheduled and it now appears after the title card.

The original conception was that the storyline of this film would take place eight years after the events of Resident Evil Apocalypse. The filmmakers ultimately decided to shorten the time gap between the two films. According to some trailers and the film's official website, the story in the Nevada desert unfolds five years after the apocalypse in Raccoon City. Since the first two films take place in 2002 (evidenced by the newspaper visible at the end of the first film) Resident Evil Extinction is placed chronologically in 2007 coinciding with the film's release year.

Sienna Guillory was offered the chance to reprise her role as Jill Valentine from Resident Evil: Apocalypse (2004), but had to turn it down due to scheduling conflicts with Eragon (2006) and the character was then written out of this sequel.

The White Queen was originally planned to appear in the first film but was excised from the screenplay. She was supposed to be the Artificial Intelligence controlling the main headquarters of Umbrella and not just the "Hive".

The name of the terrifying mutation that Dr Isaacs morphs into during the final sequence is never mentioned in the film. The creature however is lifted directly from the video games and is called Tyrant. The complete name of the deadly virus is Tyrant virus. T-virus is just an abbreviation.

The opening scene which recreates a sequence from the first film was scripted to be longer. Apart from finding the picture of the married couple , Alice would discover the rest of the clues seen in the first film, namely the hand written note or the drawer containing the weapons. Then she would enter the Red Queen's laser chamber. For pacing reasons the scene that appears in the finished film was trimmed down. It is noteworthy that after Alice sees the picture and hears a gust of wind, she simply looks at the statue. This is the only clue that the scene is just a simulation and not an exact copy of the first Resident Evil film. The original Alice asked "Hello" after she turned to the hall with the statue.

The original script implied that the reason for the global outbreak is that rats spread the infection. Apparently the fact that these rodents live mostly underground helped them survive. Although this subplot was discarded, there is still a shot of rats dwelling in the sewers of Tokyo in the final scene of the film.